A decrease in the number of functional insulin-producing β-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in β-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of β-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K⁺ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-κB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of β-cell secretory function and cell turnover. Thus, the mechanisms regulating β-cell proliferation, apoptosis, and function are inseparable processes.